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Effects of the nicotinic acetylcholine receptor agonist SIB-1508Y on object retrieval performance in MPTP-Treated monkeys Comparison with levodopa treatment.

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Effects of the Nicotinic Acetylcholine
Receptor Agonist SIB4 508Y on Object
Retrieval Performance in MPTP-Treated
Monkeys: Comparison with
Levodopa Treatment
J. S. Schneider, PhD,* M. Van Velson, BS,* F. Menzaghi, PhD,'f and G. K. Lloyd, PhDt
This study assessed the relative potencies of levodopdbenserazide and the nicotinic acetylcholine receptor agonist SIB1508Y on reversal of cognitive and motor deficits in l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine
(MPTP)-treated monkeys performing an object retrieval task. Monkeys previously taught to perform this task developed significant cognitive
deficits after chronic low-dose MPTP exposure. These monkeys then received additional MPTP treatment to superimpose
a parkinsonian movement disorder on their preexisting cognitive deficits. Levodopdbenserazide treatment significantly
improved motor aspects of object retrieval performance but did not significantly improve cognition. SIB-1508Y
(I mg/kg) alone did not result in a statistically significant improvement in cognition or motor function in symptomatic
MPTP-lesioned animals with deficits in both of these areas. However, the combination of SIB-1508Y and levodopd
benserazide caused significant improvements in both cognition and motor aspects of task performance, and did so at one
third to one sixth of the levodopa dose necessary to improve only motor function. These results suggest the potential
usefulness of SIB-1508Y and levodopa as adjunctive therapies to improve at least some of the cognitive and motor
deficits associated with Parkinson's disease.
Schneider JS, Van Velson M, Menzaghi F, Lloyd GK. Effects of the nicotinic acetylcholine receptor
agonist SIB-1508Y on object retrieval performance in MPTP-treated monkeys: comparison with
levodopa treatment. Ann Neurol 1998;43:311-317
Although Parkinson's disease (PD) is traditionally considered to be a motor disorder, it has become increasingly apparent that cognitive deficits are a common
feature. Cognitive deficits associated with PD may exist
early in the course of the disease and occur in the absence of dementia or severe
Even at the
earliest stages of the disease, neuropsychological abnormalities can be detected, including b r a d ~ p h r e n i a ~ . ~ ;
disfluency in switching from one cognitive set to another'; restlessness, irritability, and vacant, inattentive
appearance7"; difficulty sustaining mental effort'; lack
of initiative and poor concentration; and disinclination
to continue motor tasks or to put an adequate amount
of effort into a particular movement or behavior.'
In general, the cognitive deficits described in patients
with PD cover a wide range of cognitive functions. Primarily, however, they resemble problems associated
with frontal lobe dysfunction. These broadly include
problems in attention set
executive function
deficits in planning and ~equencing,~
impaired verbal
and nonverbal short-term recall,' spatial memory deficits,10 and increased distractibi1ity.l ',12 Many of these
cognitive deficits can be found at the earliest stages of
PD, and some are believed to actually predate the detection of parkinsonian motor deficits.' Thus, as motor
symptoms progress, increased motor disability may be
superimposed on earlier-appearing cognitive deficits.
In contrast to improvements in motor symptoms observed with numerous anti-Parkinson therapies, improvements in cognitive functioning are much less
clear. In one study, patients with PD performing frontal lobe tasks both on and off levodopa treatment were
found to actually have greater cognitive impairments
under conditions of dopamine replacement optimal for
producing motor improvement. l 3 In another study,
patients with advanced PD tested on frontal lobe/exec-
From the *Department of Pathology, Anatomy and Cell Biology,
Thomas Jefferson University, Philadelphia, PA, and tSIBIA Neurosciences, Inc, La Jolla, CA.
Address correspondence to Dr Schneider, Department of Pathology,
Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, 521JAH, Philadelphia, PA 19107.
'*
Received JuI 8, 1997, and in revised form Oct 10. Accepted for
publication Oct 13, 1997.
Copyright 0 1998 by the American Neurological Association 311
utive function tasks in the off levodopa condition had
greater impairments in spatial working memory, bradyphrenia, and attention set shifting than when tested on
levodopa. However, levodopa treatment had n o beneficial effects on performance of other tasks, such as delayed matching to sample, pattern and s atial recognition memory, or associative learning. Cooper and
colleagues' showed that dopamine replacement therapy
improved working memory and cognitive sequencing in
patients with PD but had no effects on other aspects of
memory or on executive function. Furthermore, administration of anticholinergic agents exacerbated existing
deficits, particularly in short-term memory.'
What is clear is that there is no consensus in the
literature on levodopa effects on cognition in PD. Although levodopa may have some effect on cognition,
many studies suggest that there may be little correlation between its positive effect on motor deficits such
as rigidity and bradykinesia and its effect on cognitive
deficits.
In view of the existing problems in simultaneously
treating both the cognitive and motor deficits of PD
with dopamine replacement therapy, the present study
investigates the use of an alternative, novel pharmacologic therapy. T h e novel nicotinic acetylcholine receptor (nAChR) agonist (S)-( -)-5-ethynyl-3-( I-methyl2-pyrrolidiny1)pyridine (SIB- 1 5 0 8 3 stimulates the release of dopamine in the striatum and frontal cortex,
norepinephrine in the hippocampus, thalamus, and
frontal cortex, and acetylcholine in the hippocampus
and the corte~.'~,'' Preliminary studies have shown
that administration of SIB-1 508Y also greatly potentiates the anti-Parkinson response to levodopa and exhibits mild anti-Parkinson effects alone in I-methyl$-phenyl-I,2,3,6-tetrahydropyridine (MPTP)-treated
monkeys with moderate-to-severe parkinsonism, when
administered orally at a dose of 8.0 mglkg." Other
studies indicated that SIB-1508Y may improve cognition in motor asymptomatic, chronic low-dose MPTPtreated monkeys." Although effects of nicotine or
nAChR agonists on cognition in patients with PD are
unknown, nicotine has improved perceptual and attentional abilities in adults with attention deficitlhyperactivity disorder2' and in patients with Alzheimer's disease.21
The present study assesses the effects of SIB-l508Y,
alone and in combination with levodopa, on performance of a detour reaching/object retrieval task in a
nonhuman primate model of PD in which both cognitive and motor deficits are expressed.
Materials and Methods
Subjects
Three adult male Macma fzscicularis monkeys (5.0-7.5 kg)
were used in this study. All animals were housed individually
in the same room with a 12-hour lighddark cycle. Animals
were maintained on a restricted diet on weekdays during
312 Annals of Neurology
Vol 43
No 3
March 1998
testing. Behavioral testing was performed with the monkey
in a testing cage located in a quiet room separate from the
monkey colony. All animal procedures were approved by the
Institutional Animal Care and Use Committee.
Behavioral Measures
These animals were previously trained to perform an object
Briefly, monretrieval task as described by us previously.22323
keys were trained to reach into a clear Plexiglas box (15 X
15 X 5 cm) with one open side, presented just outside of the
testing cage, to retrieve a food reward (apple chunk). The
open side of the box could face front, left, or right relative to
the monkey; and the reward could be placed at the front,
center, or rear edge of the box. The box could also be centered in front of the monkey or placed to the far left or right
of the testing cage. Each of 30 trials per test session differed
in the combination of reward placement, location of the
open side of the box, and the position of the box, thus affecting the cognitive or motor difficulty of the trial. Response initiation time (time between presentation of the box
and contact with it) and task completion time (time between
presentation of the box and a correct retrieval response) were
recorded. If a reward was not retrieved on the first attempt,
the number of errors made were recorded. Only cognitive
errors were assessed in this study. Cognitive errors or barrier
reaches occurred when the open side of the box faced away
from the animal and it reached for and hit a closed side of
the box rather than making a detour movement. These same
kinds of cognitive errors, indicative of impulsivity, deficits
in motor planning, and decreased ability to inhibit certain
behavioral responses, are made by animals with frontal
lobe lesions, children with attention deficit disorder, and patients with PD.24-26 Animals were originally trained to a
90% correct criterion level on this task before administration
of MPTP.
Drug Treatments
After training, animals received chronic MPTP treatment, as
described p r e v i o ~ s l yBriefly,
. ~ ~ MPTP-HCI was administered
by intramuscular injection in doses initially ranging from
0.05 to 0.075 mg/kg, two or three times per week for 24
weeks. At this point, all three monkeys developed deficits in
object retrieval task performance but had no significant motor slowing or any other signs of parkinsonism, as described
p r e v i ~ u s l y After
. ~ ~ cognitive deficits (ie, a large number of
barrier reaches) were recorded, these animals then received
additional MPTP exposure (dose range, 0.075-0.20 mglkg)
intermittently over the next 90 weeks, to produce animals
with slowly evolving motor deficits superimposed on their
cognitive deficits."
The current study was performed at least 9 months after
the last MPTP administration at a time when the animals
exhibited stable parkinsonism. These animals had been previously used in a dose-ranging study to assess the effects of
SIB-1508Y on the motor aspects of their parkinsonism" and
had prior intermittent exposure to levodopa.
In the present study, levodopa (L-dopa methyl ester,
Sigma Chemical Co, St Louis, MO) effects were assessed at
four doses (2.5, 5.0, 10.0, and 15.0 mg/kg), administered in
a random order, in each animal. Monkeys were brought to
the testing room, injected intramuscularly with 10.0 mg of
benserazide HCI (Hoffmann-LaRoche, Nutley, NJ), and, 30
minutes later, injected with levodopa. Testing took place approximately 30 minutes after levodopa administration by an
observer blind as to the drug treatment. Sterile saline was
used as the vehicle in all cases.
SIB-1508Y (synthesized and provided by SIBIA Neurosciences, Inc, La Jolla, CA) was diluted in sterile saline immediately before each drug testing session and pH was adjusted to approximately 7.0 by the addition of 1N NaOH. A
standard dose of 1.O mg/kg was administered intramuscularly, approximately 20 minutes before testing. Testing was
performed by an observer blind as to drug treatment. This
dose and the 20-minute injectiodtest interval were based on
previous results concerning drug tolerability and efficacy.
The response to SIB-1508Y in combination with levodopa
was assessed using the same standard dose of SIB-1508Y (1.0
mg/kg) in combination with either 2.5 or 5.0 mg/kg levodopa (after administration of 10 mg benserazide). In these
studies, SIB-1508Y and levodopa were administered simultaneously, 30 minutes after benserazide administration, and
testing took place approximately 30 minutes after the administration of the combined drugs.
Drug testing was performed not more than three times
per week, with minimum drug washout times of two days.
The effects of each dose of each drug were assessed twice in
each animal (although the same doses were not administered
consecutively) and these data were averaged. Saline vehicle
control sessions were interspersed between drug testing sessions, with a vehicle session included after every second or
third drug trial.
Ddta Analysis
Task performance after levodopa or SIB-1508Y alone was
compared with matched baseline and saline control performance. Task performance on combined drug trials was compared with data from levodopa trials. Because not all animals
would perform all test trials in a session, owing to motor
problems, the number of barrier reaches was expressed as
the number of barrier reaches per trial attempted. Statistical
analyses employed repeated measures t test for painvise
comparisons.
Results
All three monkeys developed deficits in performing the
object retrieval task during the first 24 weeks of
chronic low-dose MPTP exposure, as described in detail p r e v i o u ~ l y Briefly,
.~~
by week 24, monkeys made a
significantly increased number of barrier reaches per
trial (0.37 ? 0.14) as compared with normal baseline
performance (0.07 t 0.01; p < 0.05). Although cognitive errors increased, task initiation times did not significantly increase. Task completion times increased,
but because completion times were averaged for all trials (successful and nonsuccessful), this most likely reflected increased time to complete the task owing to
increased number of barrier reaches (or incorrect responses) made before retrieving the r e ~ a r d . ~During
’
this early MPTP period, the monkeys displayed few
parkinsonian features and had mean parkinsonian ratings of 3.3 +: 1.9, as assessed on a monkey parkinson
rating scale on which a total score of zero denotes a
normal animal and a score of 49 denotes the maximum
disability
After MPTP doses were elevated and monkeys developed a parkinsonian motor disorder (mean parkinson ratings of 22.7 ? 2.6), they often would not perform all task trials in a testing session. However, for
data from a testing session to be used in the analysis, a
monkey had to attempt at least 20 of the 30 trials in
the session.
In the present study, monkeys made 0.67 2 0.08
barrier reaches per trial during nondrug (baseline) trials. This did not significantly improve after levodopa
treatment, although there was a trend toward a decreased number of barrier reaches after administration
of the highest effective dose of levodopa (15 mg/kg)
(Fig 1). However, this was only observed in two of the
three monkeys, because this dose of levodopa caused
the third monkey to become unresponsive. Doses
above 15 mg/kg caused all three monkeys to become
inattentive and unresponsive and precluded testing. In
contrast to the lack of effect on cognitive errors, levodopa improved trial initiation and completion times in
a dose-dependent manner (Figs 2 and 3) with statistically significant improvements at the highest doses
tested (15 mg/kg).
SIB-1508Y (1 mg/kg) alone caused a decrease in the
number of barrier reaches made per trial, but this did
not reach statistical significance (see Fig 1). The magnitude of the effect was similar to that observed with
the high dose of levodopa. However, the combination
of this same dose of SIB-1508Y and low doses of levodopa (2.5 and 5.0 mg/kg) that were ineffective on their
own caused a significant decrease (46% t 2%) in the
number of cognitive errors produced (SIB-1508Y plus
levodopa at 2.5 mg/kg = 0.45 barrier reaches t 0.07;
SIB-1508Y plus levodopa at 5.0 mg/kg = 0.36 barrier
reaches t 0.05; see Fig 1). The effects of SIB-1508Y
plus levodopa at 2.5 mg/kg and 5.0 mg/kg were significantly different from the effects of levodopa alone
at these doses ( p < 0.01). The decrease in barrier
reaches after SIB-1508Y + levodopa at 5 mg/kg was
also significantly greater than the effect from administration of SIB-1508Y alone ( p < 0.05).
SIB-1508Y alone had no effect on trial initiation
times but in combination with a previously ineffective
dose of levodopa (5.0 mg/kg) significantly decreased
these times (0.89 second ? 0.04 vs 1.64 seconds t
0.20 during nondrug baseline trials; see Fig 2). The
combination of SIB-1508Y and levodopa at 5 mglkg
produced an improvement in initiation times significantly different from that achieved with either SIB1508Y alone o r levodopa alone at 5 mg/kg ( p < 0.05).
Likewise, SIB-1508Y alone did not significantly im-
Schneider et al: SIB-1508Y Effects in Parkinsonian Monkeys 313
Fig 1. Effects of levodopa and SIB-1508Y on the number of barrier reaches made per trial on the object retrieval task. With the
highest does of levodopa used (15.0 mg/kg L-151, there was a trend toward decreased barrier reaches, but this did not reach statistical signzycance. The same response was observed with SIB-1508Y (1.0 mg/kg 1508). However, when SIB-1508Y (1.0 mg/kg)
was co-administered with noneffective doses of levodopa (2.5 or 5.0 mglkg L-2.5, L-51, a statistically sip;fcant reduction in cognitive errors (barrier reaches) was observed. The combination of SIB-1508Y and levodopa at 5.0 mg/kg was more effective in reducing the number of barrier reaches than either SIB-1508Y alone or levodopa alone at either 5.0 or 15.0 mg/kg. Levodopa was
always administered 30 minutes after treatment with benserazide (10 mg). *p < 0.05 vs baseline; #p < 0.05 vs SIB-1508X
"p < 0.05 vs the same dose of levodopa alone; ap < 0.05 us levodopa at 15 mg/kg.
prove trial completion times. Trial completion times
were significantly decreased with the highest dose of
levodopa. When SIB-1508Y was administered in combination with a previously ineffective dose of levodopa
( 5 mg/kg), trial completion times were also significantly decreased (1.35 seconds 2 0.21 vs 2.13 seconds 2 0.18 during nondrug baseline trials) (see Fig
3 ) . However, the improvement in completion times
observed after SIB-1508Y plus levodopa at 5 mg/kg
was not significantly different from the improvement
observed after levodopa alone at the highest dose used
(ie, 15 mg/kg).
Discussion
Previous ~ o r k described
~ ~ *deficits
~ ~in ~
object
~ re~
trieval performance in motor asymptomatic MPTPtreated monkeys. The results of the present study demonstrate the long-term presence of cognitive deficits
associated with object retrieval task performance after
the subsequent development of motor signs of parkinsonism. Thus, while chronic MPTP-treated monkeys
can develop specific cognitive deficits without an accompanying parkinsonian motor disorder,22330these
cognitive deficits persist after these same animals go on
to develop parhnsonian motor deficits. These results
further validate the use of chronic MPTP-treated mon-
314 Annals of Neurology Vol 43
No 3
March 1998
keys as a model for human parkinsonism and show
that by carefully titrating MPTP exposure, monkeys
can be progressed from early to more advanced stages
of parkinsonism, with cognitive and motor deficits
analogous to humans at similar stages of PD.
Despite having mild to moderate motor deficits, all
animals were capable of performing most of the object
retrieval task trials in a testing session. Many trials, however, were marred by numerous cognitive errors or
barrier reaches. Barrier reaches reflect an impaired ability
to inhibit the tendency to make a direct line-of-sight
reach for a reward and plan sequential movements, most
likely owing to dysfunction of prefrontostriatal circ u i t ~ Monkeys
.~~
with frontal cortex lesions make numerous barrier reaches on this task, but animals with
parietal or hippocampal lesions do
Deficits in motor planning and in the ability to inhibit certain behavioral responses have also been described in patients with
PD and in patients with frontal lobe lesion^.^*^^^ The
number of barrier reaches made was unlikely a reflection
of the motor deficits in these animals, because they also
made barrier reaches when performing the task months
earlier when they were motor asymptomatic.
Dopamine replacement therapy, provided by levodopa/benserazide treatment at the doses tested in this
study, had no statistically significant effect on decreas-
Fig 2. Effects of levodopa and SIB1508Y on object retrieval trial initiation
times. With levodopa treatment, there
was a dose-dependent decrease in trial
initiation times, with the highest dose of
levodopa used (15.0 rng/kg; L-15) providing a statistically sign;ficant irnprovernent. SIB-1508Y (1.0 mg/kg) had no
effect on task initiation times. However,
when SIB-1508Y (1.0 mg/kd was coadministered with noneffective doses of
levodopa (2.5 or 5.0 mg/kg), a statistically signifcant reduction in task initiation times was observed. The combination of SIB-1508Y and levodopa at 5.0
mg/kg was more effective in decreasing
task initiation times than either SIB1508Y alone or levodopa alone at 5.0
rnglkg (L-5). Levodopa was always administered 30 minutes after treatment
with benseraide (10 mg). 9 < 0.05 us
baseline; #p < 0.05 us SIB-1508Y
alone; “p < 0.05 us the same dose of
levodopa alone.
ing the number of cognitive errors (barrier reaches), although this treatment did significantly decrease task
initiation times (ie, reduce akinesia) and task completion times (motor slowness). The finding of marked
improvement in motor symptoms with comparatively
mild improvement in cognitive function with levodopa
treatment suggests that the motor deficits of parkinson-
ism and at least some of the associated cognitive deficits may be under somewhat different neurochemical
control. Previously, we suggested that cognitive dysfunction may appear once striatal (primarily caudate)
dopamine depletions reach a certain level and that as
dopamine depletions become more severe (particularly
within the putamen), motor deficits may become su-
Figure 3. Effects of levodopa and SIB1508Y on object retrieval trial completion times. With levodopa treatment,
there was a dose-dependent decrease in
trial completion times, with the highest
dose oylevodopa used (15.0 mg/kg;
L-15) providing a statistically significant improvement. SIB-1508Y (1.0
mg/kg) had no effect on task completion times. However, when SIB-1508Y
(1.0 mg/kg) was coadrninistered with
noneffective doses of levodopa (2.5 or
5.0 mg/kg), a statistically sign&ant
decrease in task completion times was
observed. Levodopa was always administered 30 minutes after treatment with
benserazide (10 mg). 9 < 0.05 us
baseline.
Schneider et
al:
SIB-1508Y Effects in Parkinsonian Monkeys 315
perimposed on preexisting cognitive deficits.23 Although dopamine replacement therapy with levodopa
improves motor functioning, the potential dissociation
of motor from cognitive improvement suggests that the
neurochemical pathology underlying the cognitive impairment may be more complex than previously
thought. Previous studies in cognitively impaired, motor asymptomatic, chronic low-dose MPTP-treated
monkeys showed decreased norepinephrine levels and
elevated serotonin levels in some frontal cortical regions as well as in the caudate nucleus.32 It is possible
that the cognitive dysfunction in these animals is related to a combination of alterations in neurochemistry
at striatal and cortical levels and that levodopa administration cannot sufficiently normalize functioning in
all relevant neurochemical systems. It has also been
suggested that there is a critical range of dopamine
turnover for optimal prefrontal cortical cognitive functioning and that excessive dopamine turnover may lead
to cognitive i m ~ a i r m e n tAlthough
.~~
we did not see a
further impairment in cognitive performance with
higher levodopa doses due to dose-limiting motor and
nonmotor side effects, levodopa treatment alone was
not able to completely normalize the function of the
multiple cortical and subcortical neurotransmitter systems likely involved in cognition.
As in MPTP-treated monkeys, the pathophysiology
of cognitive impairment in PD remains unclear. Although some studies have suggested that changes in
dopamine levels may positivelf* or negati~ely’~
modif>.cognitive performance in patients with PD, there is
no real consensus in the literature as to the effects of
levodopa on cognitive functions in
In one study,
Kulisevsky and c o - ~ o r k e r sshowed
~~
that in both stable
levodopa responders and patients with motor fluctuations, levodopa improved response initiation times but
did not improve patients’ accuracy in performing
memory or executive function tests. Patients generally
produced a similar number of cognitive errors on and
off levodopa. This is similar to our present findings in
MPTP-treated monkeys.
The nAChR agonist SIB-1508Y alone was also unable to produce a statistically significant improvement
in cognitive performance on the object retrieval task in
these monkeys, although in low-dose, motor asymptomatic MPTP-treated monkeys this compound completely reversed deficits in delayed response and delayed
matching-to-sample paradigms. l 9 In contrast to levodopa, SIB-l508Y, at the dose used, was also incapable
of significantly improving task initiation or completion
times. When a parkinsonian disability rating scale was
used as the assessment tool, SIB-1508Y was reported to
induce a mild (15-20%) improvement.’8 However,
when a low dose of SIB-1508Y was combined with
low, ineffective doses of levodopa, significant improvements in both cognitive and motor functions were ob-
316 Annals of Neurology Vol 43
No 3
March 1998
served. Although the mechanisms underlying this effect
are unclear, there are several possible explanations. SIB1508Y (or its racemate SIB-1765F) has been shown to
induce ipsilateral circling in unilateral 6-OHDAlesioned rats, suggesting the release of striatal dopamine
in v i v ~ . ’ ~
SIB-1508Y
,~~
has also been shown to potentiate levodopa effects on reserpine-induced hypoactivity in
The weak intrinsic activity of SIB1508Y on motor function in symptomatic MPTPtreated monkeys is probably related to the severe
degree of dopamine neuron loss (>%)yo) needed
before motor deficits are evident in MPTP-treated
monkeys. Under these conditions, there is very little
substrate (ie, presynaptic dopamine) present for a releasing agent such as SIB-1508Y. O n the other hand,
the potentiation of levodopa-induced improvements
in motor functioning may involve SIB- 1508Yinduced release of dopamine formed from levodopa in
the striatum by stimulation of presynaptic nAChRs
located on dopaminergic terminals. 16,37,38
The reduction in cognitive errors obtained with coadministration of SIB-1508Y and low doses of levodopa may be explained by a combination of effects.
Low doses of levodopa alone may provide a necessary
but insufficient drive to frontostriatal circuits involved
in cognition. In these motor symptomatic monkeys,
the loss of dopamine neurons is likely more extensive
than in low-dose MPTP-treated, motor-asymptomatic
monkeys in which SIB-1508Y reverses the cognitive
deficits. Thus, the underlying dopamine substrate
may be insufficient for SIB-1508Y in spite of enhanced
acetylcholine and norepinephrine release from various
cortical and subcortical site~.’~,’’SIB-1508Y alone,
then, may provide a necessary but insufficient requirement for improved cognitive performance. In combination, these two drugs appear to provide sufficient dopaminergic and other neurochemical drive to improve
cognition in motor-symptomatic monkeys. That is, the
combination of these drugs may address the dopamine
deficiency of PD while also addressing the reduction in
noradrenergic and cholinergic function characteristic of
the disorder. This combined treatment, at least in
MPTP-treated monkeys, is superior to either treatment
alone because the combination significantly improves
both cognitive and motor performance.
In conclusion, the main results of the present study
were that chronic MPTP-treated parkinsonian monkeys continue to express cognitive deficits in the face of
progressing motor impairment. Levodopa therapy improves the motor deficits in these animals but not the
underlying cognitive disturbance. The nAChR agonist
SIB-1508Y alone had no significant effect on either
cognitive or motor impairments. However, the combination of SIB-1508Y with low, ineffective doses of
levodopa significantly improved both cognitive and
motor functioning. These results suggest that combina-
’’
tion therapy with SIB-1508Y and levodopa may provide improvement of at least some of the motor and
cognitive symptoms in patients with advanced PD,
while allowing a lowering of levodopa dosage.
This research was supported by SIBIA Neurosciences, Inc, NIH
Grant MH46531, and the Smokeless Tobacco Research Council, Inc.
The authors thank Joy Hudson for assistance in the preparation of
the manuscript and Anne Pope-Coleman for assistance in the preparation of the animals used in this study.
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acetylcholine, treatment, nicotinic, performance, objects, comparison, mptp, effect, monkey, agonists, 1508y, receptov, retrieval, treated, sib, levodopa
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